In the purpose to design novel antituberculosis (anti-TB) drugs agents against Mycobacterium tuberculosis (Mtb), we have built a molecular library around 42 Halimane Diterpenoids isolated from natural sources. Two Mtb enzymes drug targets (Mtb Mycothiol S-transferase and Mtb Homoserine transacetylase) have been adopted. The pharmacological potential was investigated through molecular docking, molecular dynamics simulation, density functional theory (gas phase and water) and ADMET analysis. Our results indicate that (2R,5R,6S)-1,2,3,4,5,6,7,8-octahydro-5-((E)-5-hydroxy-3-methylpent-3-enyl)-1,1,5,6-tetramethylnaphtha-lene-2-ol (compound 20) has displays higher docking score with each of the selected drug targets. In addition, this molecule exhibits a satisfactory drug potential activity and a good chemical reactivity. Its improved kinetic stability in the Mtb Mycothiol S-transferase enzyme reflects its suitability as a novel inhibitor of Mtb growth. This molecule has displayed a good absorption potential. Our results also show that its passive passage of the intestinal permeability barrier is more effective than that of first-line treatments (ethambutol, isoniazid). In the same way, this anti-TB druglikeness has shown to be able to cross the blood brain barrier.
References
[1]
Dye, C., Harries, A.D., Maher, D., Hosseini, S.M., Nkhoma, W. and Salaniponi, F.M. (2006) Tuberculosis. In: Jamison, D.T., Feachem, R.G., Makgoba, M.W., Bos, E.R., Baingana, F.K., Hofman, K.J. and Rogo, K.O., Eds., Disease and Mortality in Sub-Saharan Africa (2nd Edition), The International Bank for Reconstruction and Development, The World Bank, Washington DC, 179-195. http://www.ncbi.nlm.nih.gov/books/NBK2285/
[2]
Adebisi, Y.A., Agumage, I., Sylvanus, T.D., Nawaila, I.J., Ekwere, W.A., Nasiru, M., Okon, E.E., Ekpenyong, A.M. and Iii, D.E.L.P. (2019) Burden of Tuberculosis and Challenges Facing Its Eradication in West Africa. International Journal of Infection, 6, e92250. https://doi.org/10.5812/iji.92250
[3]
Atanasov, A.G., Zotchev, S.B., Dirsch, V.M. and Supuran, C.T. (2021) Natural Products in Drug Discovery: Advances and Opportunities. Nature Reviews Drug Discovery, 20, 200-216. https://doi.org/10.1038/s41573-020-00114-z
[4]
Mahesh, G., Kumar, K.A. and Reddanna, P. (2021) Overview on the Discovery and Development of Anti-Inflammatory Drugs: Should the Focus Be on Synthesis or Degradation of PGE2? Journal of Inflammation Research, 14, 253-263. https://doi.org/10.2147/JIR.S278514
[5]
Knowles, R.G. (2014) Development of Anti-Inflammatory Drugs—The Research and Development Process. Basic & Clinical Pharmacology & Toxicology, 114, 7-12. https://doi.org/10.1111/bcpt.12130
[6]
Ramos-Martín, F. and D’Amelio, N. (2023) Drug Resistance: An Incessant Fight against Evolutionary Strategies of Survival. Microbiology Research, 14, 507-542. https://doi.org/10.3390/microbiolres14020037
[7]
Halawa, E.M., Fadel, M., Al-Rabia, M.W., Abdo, M., Atwa, A.M. and Abdeen, A. (2024) Antibiotic Action and Resistance: Updated Review of Mechanisms, Spread, Influencing Factors, and Alternative Approaches for Combating Resistance. Frontiers in Pharmacology, 14, Article 1305294. https://doi.org/10.3389/fphar.2023.1305294
[8]
Grinter, S.Z. and Zou, X. (2014) Challenges, Applications, and Recent Advances of Protein-Ligand Docking in Structure-Based Drug Design. Molecules, 19, 10150-10176. https://doi.org/10.3390/molecules190710150
[9]
Rica, E., Álvarez, S. and Serratosa, F. (2021) Ligand-Based Virtual Screening Based on the Graph Edit Distance. International Journal of Molecular Sciences, 22, Article 12751. https://doi.org/10.3390/ijms222312751
[10]
Seid, A., Girma, Y., Abebe, A., Dereb, E., Kassa, M. and Berhane, N. (2023) Characteristics of TB/HIV Co-Infection and Patterns of Multidrug-Resistance Tuberculosis in the Northwest Amhara, Ethiopia. Infection and Drug Resistance, 16, 3829-3845. https://doi.org/10.2147/IDR.S412951
[11]
Bhatt, A., Quazi Syed, Z. and Singh, H. (2023) Converging Epidemics: A Narrative Review of Tuberculosis (TB) and Human Immunodeficiency Virus (HIV) Coinfection. Cureus, 15, e47624.
[12]
Sultana, Z.Z., Hoque, F.U., Beyene, J., Akhlak-Ul-Islam, M., Khan, M.H.R., Ahmed, S., Hawlader, D.H. and Hossain, A. (2021) HIV Infection and Multidrug Resistant Tuberculosis: A Systematic Review and Meta-Analysis. BMC Infectious Diseases, 21, Article No. 51. https://doi.org/10.1186/s12879-020-05749-2
[13]
Cruz-Knight, W. and Blake-Gumbs, L. (2013) Tuberculosis. Primary Care: Clinics in Office Practice, 40, 743-756. https://doi.org/10.1016/j.pop.2013.06.003
[14]
Bagcchi, S. (2023) WHO’s Global Tuberculosis Report 2022. The Lancet Microbe, 4, E20. https://doi.org/10.1016/S2666-5247(22)00359-7
[15]
Shastri, M.D., Shukla, S.D., Chong, W.C., Dua, K., Peterson, G.M., Patel, R.P., Hansbro, P.M., Eri, R. and O’Toole, R.F. (2018) Role of Oxidative Stress in the Pathology and Management of Human Tuberculosis. Oxidative Medicine and Cellular Longevity, 2018, Article ID: 7695364. https://doi.org/10.1155/2018/7695364
[16]
Carr, W. (2022) Interim Guidance: 4-Month Rifapentine-Moxifloxacin Regimen for the Treatment of Drug-Susceptible Pulmonary Tuberculosis—United States, 2022. Morbidity and Mortality Weekly Report, 71, 285-289. https://doi.org/10.15585/mmwr.mm7108a1
[17]
Nahid, P., Dorman, S.E., Alipanah, N., Barry, P.M., Brozek, J.L., Cattamanchi, A., Chaisson, L.H., Chaisson, R.E., Daley, C.L., Grzemska, M., Higashi, J.M., Ho, C.S., Hopewell, P.C., Keshavjee, S.A., Lienhardt, C., Menzies, R., Merrifield, C., Narita, M., O’Brien, R., Vernon, A., et al. (2016) Executive Summary: Official American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America Clinical Practice Guidelines: Treatment of Drug-Susceptible Tuberculosis. Clinical Infectious Diseases, 63, 853-867. https://doi.org/10.1093/cid/ciw566
[18]
Shin, H.J. and Kwon, Y.S. (2015) Treatment of Drug Susceptible Pulmonary Tuberculosis. Tuberculosis and Respiratory Diseases, 78, 161-167. https://doi.org/10.4046/trd.2015.78.3.161
[19]
Chakaya, J., Khan, M., Ntoumi, F., Aklillu, E., Fatima, R., Mwaba, P., Kapata, N., Mfinanga, S., Hasnain, S.E., Katoto, P.D.M.C., Bulabula, A.N.H., Sam-Agudu, N.A., Nachega, J.B., Tiberi, S., McHugh, T.D., Abubakar, I. and Zumla, A. (2021) Global Tuberculosis Report 2020—Reflections on the Global TB Burden, Treatment and Prevention Efforts. International Journal of Infectious Diseases, 113, S7-S12. https://doi.org/10.1016/j.ijid.2021.02.107
[20]
Khameneh, B., Fazly Bazzaz, B.S., Amani, A., Rostami, J. and Vahdati-Mashhadian, N. (2016) Combination of Anti-Tuberculosis Drugs with Vitamin C or NAC against Different Staphylococcus aureus and Mycobacterium tuberculosis Strains. Microbial Pathogenesis, 93, 83-87. https://doi.org/10.1016/j.micpath.2015.11.006
[21]
Roncero, A.M., Tobal, I.E., Moro, R.F., Díez, D. and Marcos, I.S. (2018) Halimane Diterpenoids: Sources, Structures, Nomenclature and Biological Activities. Natural Product Reports, 35, 955-991. https://doi.org/10.1039/C8NP00016F
[22]
Okerio, K.N., Kenanda, E.O. and Omosa, L.K. (2019) Antiproliferative Properties of Labdane Diterpenoids from Croton Sylvaticus Hochst against Drug Sensitive and Resistant Leukemia Cell Lines. Investigational Medicinal Chemistry and Pharmacology, 2, 1-5. https://doi.org/10.31183/imcp.2019.00031
[23]
Maroyi, A. (2017) Traditional Usage, Phytochemistry and Pharmacology of Croton sylvaticus Hochst. Ex C. Krauss. Asian Pacific Journal of Tropical Medicine, 10, 423-429. https://doi.org/10.1016/j.apjtm.2017.05.002
[24]
Stafford, G.I., Pedersen, P.D., Jäger, A.K. and Van Staden, J. (2007) Monoamine Oxidase Inhibition by Southern African Traditional Medicinal Plants. South African Journal of Botany, 73, 384-390. https://doi.org/10.1016/j.sajb.2007.03.001
[25]
Hoshino, T., Nakano, C., Ootsuka, T., Shinohara, Y. and Hara, T. (2010) Substrate Specificity of Rv3378c, an Enzyme from Mycobacterium tuberculosis, and the iNhibitory Activity of the Bicyclic Diterpenoids against Macrophagephagocytosis. Organic & Biomolecular Chemistry, 9, 2156-2165. https://doi.org/10.1039/C0OB00884B
[26]
Maugel, N., Mann, F.M., Hillwig, M.L., Peters, R.J. and Snider, B.B. (2010) Synthesis of (±)-Nosyberkol (Isotuberculosinol, Revised Structure of Edaxadiene) and (±)-Tuberculosinol. Organic Letters, 12, 2626-2629. https://doi.org/10.1021/ol100832h
[27]
Soudani, W., Hadjadj-Aoul, F.Z., Bouachrine, M. and Zaki, H. (2021) Molecular Docking of Potential Cytotoxic Alkylating Carmustine Derivatives 2-Chloroethylnitrososulfamides Analogues of 2-Chloroethylnitrosoureas. Journal of Biomolecular Structure and Dynamics, 39, 4256-4269. https://doi.org/10.1080/07391102.2020.1776638
[28]
Jayasinghe, Y.P., Banco, M.T., Lindenberger, J.J., Favrot, L., Palčeková, Z., Jackson, M., Manabe, S. and Ronning, D.R. (2023) The Mycobacterium tuberculosis Mycothiol S-Transferase Is Divalent Metal-Dependent for Mycothiol Binding and Transfer. RSC Medicinal Chemistry, 14, 491-500. https://doi.org/10.1039/D2MD00401A
Darmadi, D., Lindarto, D., Siregar, J., Widyawati, T., Rusda, M., Amin, M.M., Yusuf, F., Eyanoer, P.C., Lubis, M. and Rey, I. (2023) Study of the Molecular Dynamics Stability in the Inhibitory Interaction of Tenofovir Disoproxil Fumarate against CTLA-4 in Chronic Hepatitis B Patients. Medical Archives, 77, 227-230. https://doi.org/10.5455/medarh.2023.77.227-230
[31]
Ounthaisong, U. and Tangyuenyongwatana, P. (2017) Cross-Docking Study of Flavonoids against Tyrosinase Enzymes Using PyRx 0.8 Virtual Screening Tool. https://www.researchgate.net/publication/316546901
[32]
Morris, G.M. and Lim-Wilby, M. (2008) Molecular Docking. In: Kukol, A., Ed., Methods in Molecular Biology, Humana Press, Clifton, 365-382. https://doi.org/10.1007/978-1-59745-177-2_19
[33]
Prieto-Martínez, F.D., Arciniega, M. and Medina-Franco, J.L. (n.d.) Molecular Docking: Current Advances and Challenges. TIP. Revista Especializada En Ciencias Químico-Biológicas, 21, 1-24.
[34]
Kumar, S.A. and Bhaskar, B.L. (2019) Computational and Spectral Studies of 3,3’-(Propane-1,3-Diyl) Bis (7,8-Dimethoxy-1,3,4, 5-Tetrahydro-2H-Benzo[d]Azepin-2-one). Heliyon, 5, e02420. https://doi.org/10.1016/j.heliyon.2019.e02420
[35]
Sethi, A., Joshi, K., Sasikala, K. and Alvala, M. (2020) Molecular Docking in Modern Drug Discovery: Principles and Recent Applications. In: Gaitonde, V., Karmakar, P. and Trivedi, A., Eds., Drug Discovery and Development—New Advances, IntechOpen, Hong Kong, 1-21. https://doi.org/10.5772/intechopen.85991
[36]
Becke, A.D. (1988) Density-Functional Exchange-Energy Approximation with Correct Asymptotic Behavior. Physical Review A, 38, 3098-3100. https://doi.org/10.1103/PhysRevA.38.3098
[37]
Lee, C., Yang, W. and Parr, R.G. (1988) Development of the Colle-Salvetti Correlation-Energy Formula into a Functional of the Electron Density. Physical Review B, Condensed Matter, 37, 785-789. https://doi.org/10.1103/PhysRevB.37.785
[38]
Matin, M.A., Bhattacharjee, S., Shaikh, M.A.A., Debnath, T. and Aziz, M.A. (2020) A Density Functional Theory (DFT) Investigation on the Structure and Spectroscopic Behavior of 2-Aminoterephthalic Acid and Its Sodium Salts. Green and Sustainable Chemistry, 10, 39-55. https://doi.org/10.4236/gsc.2020.102004
[39]
Sheela, N., Muthu, S. and Sampathkrishnan, S. (2013) Molecular Orbital Studies (Hardness, Chemical Potential and Electrophilicity), Vibrational Investigation and Theoretical NBO Analysis of 4-4’-(1H-1, 2, 4-Triazol-1-yl Methylene) Dibenzonitrile Based on Abinitio and DFT Methods. Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy, 120, 237-251. https://doi.org/10.1016/j.saa.2013.10.007
[40]
De la Vega, J.G. and Miguel, B. (2003) Basis Sets for Computational Chemistry. In: Montero, L.A., Dıaz, L.A. and Bader, R., Eds., Introduction to Advanced Topics of Computational Chemistry, Citeseer, Havana, 41-80.
[41]
Shivanika, C., et al. (2022) Molecular Docking, Validation, Dynamics Simulations, and Pharmacokinetic Prediction of Natural Compounds against the SARS-CoV-2 Main-Protease. Journal of Biomolecular Structure & Dynamics, 40, 585-611.
[42]
Liu, H., Jin, Y. and Ding, H. (2023) MDBuilder: A PyMOL Plugin for the Preparation of Molecular Dynamics Simulations. Briefings in Bioinformatics, 24, bbad057. https://doi.org/10.1093/bib/bbad057
[43]
El Aissouq, A., Chedadi, O., Bouachrine, M. and Ouammou, A. (2021) Identification of Novel SARS-CoV-2 Inhibitors: A Structure-Based Virtual Screening Approach. Journal of Chemistry, 2021, Article ID: 1901484. https://doi.org/10.1155/2021/1901484
[44]
Guan, L., Yang, H., Cai, Y., Sun, L., Di, P., Li, W., Liu, G. and Tang, Y. (2018) ADMET-Score—A Comprehensive Scoring Function for Evaluation of Chemical Drug-Likeness. MedChemComm, 10, 1-11. https://doi.org/10.1039/C8MD00472B
[45]
Baldi, A. (2010) Computational Approaches for Drug Design and Discovery: An Overview. Systematic Reviews in Pharmacy, 1, 99. https://doi.org/10.4103/0975-8453.59519
[46]
Flores-Holguín, N., Frau, J. and Glossman-Mitnik, D. (2021) Computational Pharmacokinetics Report, ADMET Study and Conceptual DFT-Based Estimation of the Chemical Reactivity Properties of Marine Cyclopeptides. ChemistryOpen, 10, 1142-1149. https://doi.org/10.1002/open.202100178
[47]
Moto Ongagna, J., Tamafo Fouegue, A.D., Ateba Amana, B., Mouzong D’ambassa, G., Zobo Mfomo, J., Mbaze Meva’A, L. and Bikele Mama, D. (2020) B3LYP, M06 and B3PW91 DFT Assignment of nd8 Metal-Bis-(N-Heterocyclic Carbene) Complexes. Journal of Molecular Modeling, 26, Article No. 246. https://doi.org/10.1007/s00894-020-04500-7
[48]
Bai, G., Pan, Y., Zhang, Y., Li, Y., Wang, J., Wang, Y., Teng, W., Jin, G., Geng, F. and Cao, J. (2023) Research Advances of Molecular Docking and Molecular Dynamic Simulation in Recognizing Interaction between Muscle Proteins and Exogenous Additives. Food Chemistry, 429, Article ID: 136836. https://doi.org/10.1016/j.foodchem.2023.136836
[49]
Darden, T., York, D. and Pedersen, L. (1993) Particle Mesh Ewald: An N∙log(N) Method for Ewald Sums in Large Systems. The Journal of Chemical Physics, 98, 10089-10092. https://doi.org/10.1063/1.464397
[50]
Antonini, G., Civera, M., Lal, K., Mazzotta, S., Varrot, A., Bernardi, A. and Belvisi, L. (2023) Glycomimetic Antagonists of BC2L-C Lectin: Insights from Molecular Dynamics Simulations. Frontiers in Molecular Biosciences, 10, Article 1201630. https://doi.org/10.3389/fmolb.2023.1201630
[51]
Brańka, A. (2000) Nosé-Hoover Chain Method for Nonequilibrium Molecular Dynamics Simulation. Physical Review E, 61, 4769-4773. https://doi.org/10.1103/PhysRevE.61.4769
[52]
Bekono, B.D., Esmel, A.E., Dali, B., Ntie-Kang, F., Keita, M., Owono, L.C. and Megnassan, E. (2021) Computer-Aided Design of Peptidomimetic Inhibitors of Falcipain-3: QSAR and Pharmacophore Models. Scientia Pharmaceutica, 89, Article 44. https://doi.org/10.3390/scipharm89040044
[53]
Bekono, B.D., Sona, A.N., Eni, D.B., Owono, L.C.O., Megnassan, E. and Ntie-Kang, F. (2021) 13 Molecular Mechanics Approaches for Rational Drug Design: Forcefields and Solvation Models. In: Ramasami, P., Ed., Computational Chemistry: Applications and New Technologies, De Gruyter, Berlin, 233-254. https://doi.org/10.1515/9783110682045-013
[54]
Zhu, X., Lopes, P.E. and Mackerell Jr., A.D. (2012) Recent Developments and Applications of the CHARMM Force Fields. WIREs Computational Molecular Science, 2, 167-185. https://doi.org/10.1002/wcms.74
[55]
Rossino, G., Rui, M., Pozzetti, L., Schepmann, D., Wünsch, B., Zampieri, D., Pellavio, G., Laforenza, U., Rinaldi, S., Colombo, G., Morelli, L., Linciano, P., Rossi, D. and Collina, S. (2020) Setup and Validation of a Reliable Docking Protocol for the Development of Neuroprotective Agents by Targeting the Sigma-1 Receptor (S1R). International Journal of Molecular Sciences, 21, Article 7708. https://doi.org/10.3390/ijms21207708
[56]
Wang, Y., Jiao, Q., Wang, J., Cai, X., Zhao, W. and Cui, X. (2023) Prediction of Protein-Ligand Binding Affinity with Deep Learning. Computational and Structural Biotechnology Journal, 21, 5796-5806. https://doi.org/10.1016/j.csbj.2023.11.009
[57]
Qasaymeh, R.M., Rotondo, D., Oosthuizen, C.B., Lall, N. and Seidel, V. (2019) Predictive Binding Affinity of Plant-Derived Natural Products towards the Protein Kinase G Enzyme of Mycobacterium tuberculosis (MtPknG). Plants, 8, Article 477. https://doi.org/10.3390/plants8110477
[58]
Yonezawa, T., Shingu, H. and Fukui, K. (1952) A Molecular Orbital Theory of Reactivity in Aromatic Hydrocarbons. The Journal of Chemical Physics, 50, 722-725.
[59]
Miar, M., Shiroudi, A., Pourshamsian, K., Oliaey, A.R. and Hatamjafari, F. (2021) Theoretical Investigations on the HOMO–LUMO Gap and Global Reactivity Descriptor Studies, Natural Bond Orbital, and Nucleus-Independent Chemical Shifts Analyses of 3-Phenylbenzo[d]Thiazole-2(3H)-Imine and Its Para-Substituted Derivatives: Solvent and Substituent Effects. Journal of Chemical Research, 45, 147-158. https://doi.org/10.1177/1747519820932091
[60]
Belviso, S., Santoro, E., Lelj, F., Casarini, D., Villani, C., Franzini, R. and Superchi, S. (2018) Stereochemical Stability and Absolute Configuration of Atropisomeric Alkylthioporphyrazines by Dynamic NMR and HPLC Studies and Computational Analysis of HPLC-ECD Recorded Spectra. European Journal of Organic Chemistry, 2018, 4029-4037. https://doi.org/10.1002/ejoc.201800553
[61]
Geerlings, P., De Proft, F. and Langenaeker, W. (2003) Conceptual Density Functional Theory. Chemical Reviews, 103, 1793-1874. https://doi.org/10.1021/cr990029p
[62]
Parr, R.G., Szentpály, L.V. and Liu, S. (1999) Electrophilicity Index. Journal of the American Chemical Society, 121, 1922-1924. https://doi.org/10.1021/ja983494x
[63]
Kralj, S., Jukič, M. and Bren, U. (2023) Molecular Filters in Medicinal Chemistry. Encyclopedia, 3, 501-511. https://doi.org/10.3390/encyclopedia3020035
[64]
Lipinski, C.A., Lombardo, F., Dominy, B.W. and Feeney, P.J. (2001) Experimental and Computational Approaches to Estimate Solubility and Permeability in Drug Discovery and Development Settings. Advanced Drug Delivery Reviews, 46, 3-26. https://doi.org/10.1016/S0169-409X(00)00129-0
[65]
Jia, C.Y., Li, J.Y., Hao, G.F. and Yang, G.F. (2020) A Drug-Likeness Toolbox Facilitates ADMET Study in Drug Discovery. Drug Discovery Today, 25, 248-258. https://doi.org/10.1016/j.drudis.2019.10.014
[66]
Dobson, P.D. and Kell, D.B. (2008) Carrier-Mediated Cellular Uptake of Pharmaceutical Drugs: An Exception or the Rule? Nature Reviews Drug Discovery, 7, 205-220. https://doi.org/10.1038/nrd2438
[67]
Muegge, I., Heald, S.L. and Brittelli, D. (2001) Simple Selection Criteria for Drug-Like Chemical Matter. Journal of Medicinal Chemistry, 44, 1841-1846. https://doi.org/10.1021/jm015507e
[68]
Gupta, M., Lee, H.J., Barden, C.J. and Weaver, D.F. (2019) The Blood-Brain Barrier (BBB) Score. Journal of Medicinal Chemistry, 62, 9824-9836. https://doi.org/10.1021/acs.jmedchem.9b01220
[69]
Karplus, M. and Petsko, G.A. (1990) Molecular Dynamics Simulations in Biology. Nature, 347, 631-639. https://doi.org/10.1038/347631a0
[70]
Hansson, T., Oostenbrink, C. and van Gunsteren, W. (2002) Molecular Dynamics Simulations. Current Opinion in Structural Biology, 12, 190-196. https://doi.org/10.1016/S0959-440X(02)00308-1
